1. Clinical Trials of Pandemic Vaccines: Key Issues John Treanor University of Rochester Rochester, NY

2. Inactivated vaccine approach Proven technology - Used successfully in 1957 and 1968 - Abundant efficacy data in both pandemic and interpandemic years - Very safe, with large safety database Manufacturing capacity exists in potentially large scale Licensing would be relatively straight- forward

3. Inactivated vaccine approach Unlikely to induce mucosal immunity - May be less effective in preventing spread Protection may be strain specific - Little if any cellular immune response Requires multiple doses Manufacturing capacity limited by availability of eggs and capacity for expansion limited - Cell culture strategies might circumvent this problem

4. Recent clinical evaluations of potential pandemic viruses Duck Singapore/97 (H5N3) as a vaccine for Hong Kong/97 Recombinant, baculovirus-expressed HA of A/Hong Kong/156/97 (H5) Whole virion A/Singapore/1/57 (H2N2) and A/Hong Kong/1073/99 (H9N2) Whole virion and subunit A/Hong Kong/1073 (H9N2)

5. Egg-grown Duck/Singapore No adjuvant MF59 adjuvant 100 7.5 ug HA 15 ug HA 80 30 ug HA 60 40 20 00 0214202142 Study day Nicholson et al Lancet 357:1937, 2001

6. Egg-grown Duck/Singapore Duck Singapore Hong Kong 100 7.5 ug HA 15 ug HA 80 30 ug HA 60 40 20 00 0214202142 Study day Nicholson et al Lancet 357:1937, 2001

7. Reimmunization with Duck/Singapore 300 250 200 150 100 50 0 MF59 Stephenson et al, Vaccine 21:1687, 2003 Base Day 42 16 mo Day 21 Plain

8. Key issues [1] Development of standardized, validated surrogate markers of protection Responses to inactivated vaccines may be very strain specific - evaluation of strategies to broaden responses Adjuvants should be evaluated. Ratio of antigen to adjuvant may be important Pre-pandemic priming dose with heterologous variants should be explored Dose responses relationships may not be obvious

9. Recombinant rHA H5 Vaccine Insect cell expressing rHA RBCs Purified rHA H5 SDS-PAGE

10. Phase I evaluation of rH5 Randomized to interval between doses (21, 28, or 42 days) and then to dose groups (90 ug, 45 ug, 25 ug, 90/10 ug, placebo) - Total of 15 groups Vaccine or placebo administered in total of 1 mL by i.m. injection Sera before and 14 days after dose 1, and before and 7, 14, 21, and 28 days after dose 2